Palladium-catalyzed heteroannulation leading to heterocyclic structures with two heteroatoms: A highly regio- and stereoselective synthesis of (Z)-4-alkyl-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4,-benzoxazines and (Z)-3-alkyl(aryl)idene-4-tosyl-3,4-dihydro-2H-1,4-benzoxazines

Article abstract of DOI:10.1021/jo000826j

A highly convenient method has been developed for the synthesis of (Z)-4-alkyl-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4-benzoxazines 9 and (Z)-3-alkyl(aryl)idene-4-tosyl-3,4-dihydro-2H-1,4-benzoxazines 34-38 through palladium - copper-catalyzed reactions. Aryl halides 7 reacted with 2-[Nalkyl(benzyl)-N-prop-2′-ynyl]aminophenyl tosylate 6 in the presence of (PPh₃)₂PdCl₂ (3 mol %), CuI(5 mol %) in triethylamine at room temperature to yield 2-[N-alkyl(benzyl)-N-(3-aryl-prop-2′-ynyl)]aminophenyl tosylates 8 in extremely good yields (72-96%). The latter could then be cyclized with KOH in ethanol - water to Z-9 in a highly regio- and stereoselective manner. Similarly, palladium copper-catalyzed reaction of 2-(prop-2′-ynyloxy)aniline (21) with aryl iodides 7 led to 22-26 which after tosylation and cyclization with cuprous iodide in CH₃CN in the presence of K₂CO₃ and Bu_4-NBr led to the (Z)-3-alkyl(aryl)idene-4-tosyl 3,4-dihydro-2H-1,4-benzoxazines 34-38 in good overall yields. The Z-stereochemistry of the products was established from ¹H NMR spectra, ³J_CH values (between vinylic proton and methylenic carbon of the heterocyclic ring), NOE experiments, and X-ray analysis· The method was also found to be suitable for the synthesis of bis(benzoxazinylated) derivatives 17, 39, and 2-alkyl-3,4-dihydro-2H-1,4-benzoxazines 18. Our method for the synthesis of 3,4-dihydro-2H-1,4-benzoxazines is highly efficacious, using easily available starting materials under very mild conditions. Also the synthesis of some novel 5-substituted uracil derivatives 40 and 41 containing the benzoxazinyl moiety and of potential biological interest is being reported.

Full text of DOI:10.1021/jo000826j

20
J . Org. Chem. 2001, 66, 20-29
P a lla d iu m -Ca ta lyzed Heter oa n n u la tion Lea d in g to Heter ocyclic
Str u ctu r es w ith Tw o Heter oa tom s: A High ly Regio- a n d
Ster eoselective Syn th esis of
(Z)-4-Alk yl-2-a lk yl(a r yl)id en e-3,4-d ih yd r o-2H-1,4-ben zoxa zin es a n d
(Z)-3-Alk yl(a r yl)id en e-4-tosyl-3,4-d ih yd r o-2H-1,4-ben zoxa zin es†
Nitya G. Kundu,* Gopeswar Chaudhuri, and Anup Upadhyay‡
Department of Organic Chemistry, Indian Association for the Cultivation of Science, J adavpur,
Calcutta - 700 032, India
ocngk@mahendra.iacs.res.in
Received May 30, 2000
A highly convenient method has been developed for the synthesis of (Z)-4-alkyl-2-alkyl(aryl)idene-
3,4-dihydro-2H-1,4-benzoxazines 9 and (Z)-3-alkyl(aryl)idene-4-tosyl-3,4-dihydro-2H-1,4-benzox-
azines 34-38 through palladium-copper-catalyzed reactions. Aryl halides 7 reacted with 2-[N-
alkyl(benzyl)-N-prop-2′-ynyl]aminophenyl tosylate 6 in the presence of (PPh3)2PdCl2 (3 mol %), CuI(5
mol %) in triethylamine at room temperature to yield 2-[N-alkyl(benzyl)-N-(3-aryl-prop-2′-ynyl)]-
aminophenyl tosylates 8 in extremely good yields (72-96%). The latter could then be cyclized with
KOH in ethanol-water to Z-9 in a highly regio- and stereoselective manner. Similarly, palladium-
copper-catalyzed reaction of 2-(prop-2′-ynyloxy)aniline (21) with aryl iodides 7 led to 22-26 which
after tosylation and cyclization with cuprous iodide in CH3CN in the presence of K2CO3 and Bu4-
NBr led to the (Z)-3-alkyl(aryl)idene-4-tosyl 3,4-dihydro-2H-1,4-benzoxazines 34-38 in good overall
1
3
yields. The Z-stereochemistry of the products was established from H NMR spectra, J CH values
(between vinylic proton and methylenic carbon of the heterocyclic ring), NOE experiments, and
X-ray analysis. The method was also found to be suitable for the synthesis of bis(benzoxazinylated)
derivatives 17, 39, and 2-alkyl-3,4-dihydro-2H-1,4-benzoxazines 18. Our method for the synthesis
of 3,4-dihydro-2H-1,4-benzoxazines is highly efficacious, using easily available starting materials
under very mild conditions. Also the synthesis of some novel 5-substituted uracil derivatives 40
and 41 containing the benzoxazinyl moiety and of potential biological interest is being reported.
The 2H-1,4-benzoxazine1 structure has been the inte-
against KB carcinoma cells in vitro6 and antitumor
activity toward tumor-bearing mice in vivo.7 Various
benzoxazine derivatives have shown to have interesting
pharmacological properties. Thus, nazasetran hydrochlo-
ride (Y-25130), N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-
3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carbox-
amide hydrochloride, a highly potent 5-HT3 receptor
antagonist, has been reported as an antiemetic agent for
severe nausea and vomiting induced by chemotherapy
gral part of many naturally occurring substances. For
example, blepharin, [(2R)-2-â-D-glucopyranosyloxy-2H-
1,4-benzoxazine-3(4H)-one] (I), and other glycosides of the
2-hydroxy-2H-1,4-benzoxazine-3(4H)-one skeleton have
been found to occur in gramineous plants such as maize,
wheat, rye, rice, etc., and have been suggested to act as
plant resistance factors against microbial diseases and
insects.2
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Similarly, actinomycin-D, an anticancer drug isolated
from streptomyces, has the benzoxazine structural moiety
as part of the chromophoric unit of the drug molecule.3
The 1,4-benzoxazine structure has also been found in the
antibiotic C-1027,4 a novel antitumor chromoprotein,
isolated from the broth filtrate of Streptomyces glo-
bisporus C-10275 which shows extreme cytotoxic potency
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Yamada, Y.; Marunaka, T. J . Antibiot. 1988, 41, 1575. (b) Otani, T.;
Minami, Y.; Marumaka, T.; Zhang, R.; Xie, M.-Y. J . Antibiot. 1988,
41, 1580.
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† Dedicated to Professor Dr. (Mrs.) Asima Chatterjee, Department
of Chemistry, Calcutta University, Calcutta, on the occasion of her 83rd
birthday in the beginning year of the new millennium.
‡ In part only.
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In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W., Eds.; Pergamon Press: Oxford, 1984; Vol. 3, pp 995-1038.
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10.1021/jo000826j CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/09/2000

Palladium-Catalyzed Heteroannulation
J . Org. Chem., Vol. 66, No. 1, 2001 21
in cancer patients.8 Several 3,4-dihydro-2H-1,4-benzox-
azine derivatives have been reported to be potassium
channel openers(PCOs)in vascular smooth muscle.9 Ben-
zoxazino-rifamycin KRM-1648 has been shown to have
in vitro and in vivo activities against Mycobacterium
tuberculosis.10 Recently, a number of methotrexate de-
rivatives incorporating the benzoxazine moiety have been
synthesized. Some of these compounds have proved to
be potent and safe candidate antirheumatic agents.11
Moreover, benzoxazine derivatives have been used as
intermediates for the synthesis of other heterocyclic
structures of biological importance.12,13 Photochemical
transformation of 1,4-benzoxazines to other heterocyclic
structures have also been reported.14
Due to the importance of 2H-1,4-benzoxazine structure,
several syntheses of this compound and its derivatives
have been reported by various investigators over the last
few decades.1,15-17 However, most of the methods reported
were targeted toward the synthesis of some specific
benzoxazine derivative and lacked generality and hence
were of limited synthetic utility. Moreover, recent devel-
opments in the field of metal-catalyzed reactions have
almost been completely ignored to develop general meth-
ods for the synthesis of benzoxazine compounds.
Sch em e 1
strategies utilizing palladium-catalyzed reactions have
led to the synthesis of various carbocyclic20 and hetero-
cyclic structures.21 Our own efforts in the field of pal-
ladium-catalyzed heteroannulation reactions have been
the use of terminal alkynes with aromatic iodo com-
pounds22 having a nucleophilic group in the ortho-position
to the iodo-substituent, and these have led to the
synthesis of various benzo-fused heterocyclic systems
with one heteroatom, e.g., benzofurans,23 phthalides,24
quinolines and quinolones,25 isoindolinones,26 and fla-
vanones,27 which are the integral part of many naturally
occurring and biologically active compounds.
Very recently, in a different strategy we have used
monoprop-2-ynylated catechol 1 as the source of both
terminal alkyne moiety and the nucleophilic center and
have utilized its reaction with aromatic iodo compounds
2 under palladium-copper catalysis to develop a general
and a highly regio- and stereoselective synthesis of (Z)-
2,3-dihydro-2-alkylidene-1,4-benzodioxins 3 (Scheme 1).28
In continuation of those studies, we felt that it will be
interesting to develop general methods for the synthesis
of other benzo-fused heterocycles containing two heteroa-
toms in the same ring following the above strategy.
Herein, we report our results on the synthesis of (Z)-2-
alkylidene-3,4-dihydro-2H-1,4-benzoxazines29 and (Z)-3-
alkylidene-3,4-dihydro-2H-1,4-benzoxazines.
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tion of olefins (Heck reaction)18 and cross-coupling reac-
tions19 have been of greatest significance in the formation
of carbon-carbon bonds. The application of different
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(29) A preliminary report on the synthesis of (Z)-2-alkylidene
(arylidene)-3,4-dihydro-2H-1,4-benzoxazines has appeared: Chaudhuri,
G.; Chowdhury, C.; Kundu, N. G. Synlett 1998, 1273. The compounds
were reported as derivatives of 2,3-dihydro-4H-benzoxazine isomer.

22 J . Org. Chem., Vol. 66, No. 1, 2001
Kundu et al.
Sch em e 2a
the yields considerably. We have also explored the role
of various solvents (e.g. CH3CN, DMF, Et3N) in the
palladium-catalyzed reactions and found triethylamine
to be the most effective solvent which could act also as a
base. The use of DMF with triethylamine led to the
formation of much-colored materials which lowered the
yields of the disubstituted alkynes 8. A variety of aryl
iodides were utilized for the arylation of the terminal
alkyne 6 most effecively (yields 72-96%). It was observed
that both aromatic and heteroaromatic iodides were
equally effective. However, electron-donating substituent
(e.g., OMe) reduced the yield to some extent (72-80%).
The disubstituted alkynes 8 did not cyclize to the
benzoxazines 9 under the palladium-copper-catalyzed
condition of their formation as was observed in the case
of the synthesis of benzodioxans.28 The compounds 8
neither could be cyclized with CuI in triethylamine.31
However, 8 could be smoothly cyclized with KOH in
ethanol-water by refluxing for 8-10 h under argon
atmosphere. The yields of the benzoxazines were usually
high (70-93%) except in case of the o-nitro compound
(entry 10) where the yield of the cyclized product was
found to be extremely poor (35%) due to the formation of
much-colored materials. The presence of a benzyl or an
alkyl group on the N-atom in 8 was found to be essential
for the successful cyclization of 8 to the benzoxazines 9.
Thus, it was observed that 2-(N-prop-2′-ynyl)aminophe-
nyl tosylate 5 could be C-arylated to 11 with aryl iodides
under palladium-copper catalysis (Scheme 3).
a
Reaction conditions: (i) TsCl (1 equiv, 0.01 mmol), Et3N (0.01
mmol), CH2Cl2 (20 mL). (ii) Propargyl bromide (1.2 equiv, 22.8
mmol), K2CO3 (19.0 mmol), DMF (35 mL), 80 °C, 48 h. (iii) Benzyl
bromide (1.5 equiv, 9.94 mmol), K2CO3 (6.63mmol), DMF (20 mL),
80 °C, 48 h. (iv) (PPh3)2PdCl2 (3.0 mol %), CuI (5.0 mol %), Et3N
(12 mL), stirring at room temperature, 16 h. (v) KOH (19 equiv),
EtOH/H2O, 80 °C, 8-10 h.
Resu lts a n d Discu ssion
However, compounds 11 did not cyclize to the benzox-
azines when refluxed with KOH in EtOH. Similarly,
2-(N-prop-2′-ynyl)amino phenol 12, obtained from 5 by
alkaline hydrolysis, underwent the usual arylation with
aryl iodides 7 under palladium-copper catalysis (albeit
at a higher temperature, e.g., 100 °C for 16 h). However,
no cyclic products (benzoxazines) were obtained under
this condition. This is in contrast to the case of benzo-
1,4-dioxans where palladium-copper-catalyzed arylation
and cyclization to benzo-1,4-dioxans took place in one
step.28 Cyclization of compounds 13 could neither be
effected with NaOEt in EtOH at 80 °C for 16-24 h nor
with CuI (10-40 mol %) in Et3N31 at 80 °C for 16-48 h.
Finally, the disubstituted alkynes 13 could be cyclized
with Pd(OAc)2 (5 mol %), LiCl (0.5 equiv), and K2CO3 (2.5
equiv) in DMF at 100 °C for 16 h32 to the benzoxazines
14 only in poor yields (10-20%). However, we have
already observed that the N-benzylated or N-alkylated
disubstituted alkynes 8 underwent smooth cyclization to
9 with KOH in EtOH/H2O.
Na tu r e of th e P r od u cts, Str u ctu r e, a n d Ster eo-
ch em istr y. 4-Alkyl(benzyl)-2-alkyl(aryl)idene-3,4-dihy-
dro-2H-1,4-benzoxazines 9 were found to be highly
unstable in halogenated solvents such as CHCl3, CH2-
Cl2, and CDCl3. Therefore, workup, purification, and
crystallization were done either with diethyl ether-
petroleum ether (bp 60-80 °C) or with diethyl ether-
ethyl acetate. Column chromatography was done on
neutral alumina instead of silica gel. The structure of the
benzoxazines were established from analytical and spec-
troscopic (IR, 1H NMR, 13C NMR, and mass spectral)
data. In IR spectra, the absorption peaks at 1680-1660
and 1600 cm-1 indicated the presence of conjugated
2-[N-Alkyl (or benzyl)-N-prop-2′-ynyl)aminophenyl to-
sylate 6 was treated with aryl iodides 7 in the presence
of bis(triphenylphosphine)palladium(II) chloride (3 mol
%) and cuprous iodide (5 mol %) in triethylamine at room
temperature for 16 h where the disubstituted alkynes 8
were produced. These did not undergo cyclization under
the palladium-copper catalysis condition (in contrast to
the case of benzodioxans). However, they could be cyclized
by refluxing with KOH in ethanol/H2O for 8-10 h to the
(Z)-2-alkylidene-4-alkyl(benzyl)-3,4-dihydro-2H-1,4-ben-
zoxazines 9 in excellent yields (Scheme 2, Table 1).
2-[N-Alkyl (or, benzyl)-N-prop-2′-ynyl)aminophenyl to-
sylate 6 was used as the substrate for the palladium-
catalyzed reaction with aryl iodides 7. Compound 6 was
synthesized starting from ortho-aminophenol which was
O-tosylated with p-toluenesulfonyl chloride in the pres-
ence of triethylamine in dichloromethane to yield 4.30
Tosylation in the presence of pyridine leads to N-
tosylation. Compound 4 was then propargylated with
propargyl bromide in the presence of K2CO3 in DMF to
yield compound 5. 2-(N-Prop-2′-ynyl)aminophenyl tosyl-
ate 5 was then benzylated or alkylated to compound 6.
The palladium-catalyzed reaction of 6 with aryl iodides
7 was carried out with bis(triphenylphosphine)palladium-
(II) chloride as the catalyst of choice and cuprous iodide
as the cocatalyst. The presence of the O-tosyl group was
found to be essential since any prior removal of it through
alkaline hydrolysis led to spontaneous cyclization to 3,4-
dihydro-2H-2-methylene-1,4-benzoxazine (10) (Scheme
2). The palladium-catalyzed reactions of 6 with aryl
iodides 7 could be carried out under very mild conditions.
The reactions were usually carried out at room temper-
ature in an inert atmosphere (N2 or argon) for 16 h.
Heating at 60 °C reduced the time of reaction but lowered
(31) (a) Chaudhuri, G.; Kundu, N. G. J . Chem. Soc., Perkin Trans.
1 2000, 775. (b) Nandi, B.; Kundu, N. G. Org. Lett. 2000, 2, 235.
(32) Larock, R. C.; Yum, E. K. J . Am. Chem. Soc. 1991, 113, 6689.
(30) Kurita, K. Chem. Ind. (London) 1974, 345.

Palladium-Catalyzed Heteroannulation
J . Org. Chem., Vol. 66, No. 1, 2001 23
Ta ble 1. Rea ction of 2-[N-Ben zyl(or a lk yl)-N-p r op -2′-yn yl]a m in o P h en yl Tosyla te 6 w ith Ar yl Iod id es 7 in P r esen ce of
P a lla d iu m Ca ta lyst, Cop p er (I) Iod id e, a n d Et3N a n d Su bsequ en t Tr ea tm en t w ith KOH in EtOH/H2O (Sch em e 2)
prop-2-ynylated
aminophenyl
tosylates, 6, R
2-alkylidene-
benzoxazines 9,
(%)b, [%]c
aryl iodides 7,
disubstituted alkynes 8,
entry
Ar
Ar (%)a
1
2
3
4
5
6
7
8
9
Bn, 6a
Bn, 6a
Bn, 6a
Bn, 6a
Bn, 6a
Bn, 6a
Bn, 6a
Me, 6b
Me, 6b
Me, 6b
Et, 6c
C6H5, 7a
3-ClC6H4, 7b
C6H5, 8a (92)
3-ClC6H4, 8b (96)
9a (93) [85]
9b (70) [69]
9c (82) [59]
9d (93) [83]
9e (87) [83]
9f (84) [79]
9g (76) [61]
9h (70) [59]
9i (75) [71]
9j (35) [32]
9k (93) [84]
2-MeOC6H4, 7c
4-MeC6H4, 7d
1-naphthyl, 7e
2-thienyl, 7f
2,4-dimethoxy-5-pyrimidinyl, 7g
C6H5, 7a
3-ClC6H4, 7b
2-O2NC6H4, 7h
3-ClC6H4, 7b
2-MeOC6H4, 8c (72)
4-MeC6H4, 8d (89)
1-naphthyl, 8e (95)
2-thienyl, 8f (94)
2,4-dimethoxy-5-pyrimidinyl, 8g (80)
C6H5, 8h (84)
3-ClC6H4, 8i (95)
2-O2NC6H4, 8j (92)
3-ClC6H4, 8k (90)
10
11
a
b
The yields refer to chromatographically isolated pure materials and based on compound 7. Yields of pure benzoxazines 9 are based
on 8. c Overall yields of benzoxazines are based on 7.
Sch em e 3a
Sch em e 4
a
Reaction conditions: (i) ArI (0.83 equiv), (PPh3)2PdCl2 (0.02
mmol), CuI (0.04 mmol), Et3N (9 mL). (ii) KOH in EtOH/H2O, 80
°C, 8-10 h; (iii) same as (ii). (iv) same as (i) (v) Pd(OAc)2(5 mol %,
0.12 mmol), LiCl (1.21 mmol), K2CO3 (6.02 mmol), DMF, 100 °C,
16 h.
for compounds 9 in the range of 3.65-4.3 Hz confirming
the Z-stereochemistry. Further validation of the Z-
stereochemistry was obtained from NOE experiments.
When methylenic protons of the heterocyclic ring of
compounds 9 were irradiated, a strong enhancement of
the vinylic proton signal of the exocyclic double bond was
noticed and vice versa, supporting the Z-stereochemistry.
Finally, an X-ray diffraction study on compound 9c was
carried out which supported its structure and the Z-
stereochemistry.35
double bonds. In the 1H NMR spectra, the exocyclic
vinylic hydrogen could be easily seen at δ 5.29-6.03 and
the methylenic group (-N-CH2-) of the heterocyclic ring
was noted at δ 3.65-3.84 as singlets, confirming the
benzoxazine structures. This was further confirmed by
the 13C NMR data at δc 48.7-52.5 ppm for the N-CH2
of the heterocyclic ring and δc 99.7-104.7 ppm for the
methine carbon (CdCH) of the exocyclic bond of com-
pounds 9.
Mech a n ism . The mechanism of the reaction can be
shown as envisaged in Scheme 4.
The heteroannulation process was found to be com-
pletely regio- and stereoselective. No seven-membered
ring compounds or compounds of E-stereochemistry were
isolated. The Z-stereochemistry of the compounds 9
follows from the chemical shift position of the vinylic
hydrogen at δH 5.29-6.03. If the compounds had the
E-stereochemistry, it was expected that due to the
deshielding effect of the proximal ring oxygen atom, the
δH values of the vinylic hydrogen will be much higher
than 6 ppm.33 The Z-stereochemistry was also assigned
The Pd0(A) generated22c from (Ph3P)2PdCl2 will undergo
oxidative addition with ArX (7) to produce ArPdX (B).
The ArPdX on transmetalation with the Cu-acetylide (C)
derived from 6 will lead to D which on reductive elimina-
tion of palladium will generate the disubstituted alkynes
8. On alkaline hydrolysis of 8, the phenoxide ion (E)
generated undergoes an exo-dig attack on the triple bond
forming the (Z)-9 in a highly stereoselective manner.
3
from the consideration of the J CH values for the interac-
Scop e of th e Rea ction
tion between the vinylic proton and the methylenic
Syn t h esis of Bis(b en zoxa zin yl) Der iva t ives. We
have extended the scope of the reaction by synthesizing
bis(benzoxazinyl) derivatives. Thus, the treatment of 6
with di-iodo compounds 15 under palladium-copper
carbon (N-CH2) of the heterocyclic ring. It has been
3
reported in the literature34 that the J CH values more
than 7 Hz or less than 5 Hz could be attributed to E -or
Z-isomers, respectively. We have observed the 3J CH values
(33) In case of (E)- and (Z)-isomers, different chemical shift values
of vinylic proton of exocyclic double bond due to deshielding effect of
oxygen of some heterocyclic rings have been invoked to account for
the results: (a) J ager, V.; Gunther, H. J . Tetrahedron Lett. 1977, 2543.
(b) Yamamoto, M. J . Chem. Soc., Chem. Commun. 1978, 649. (c) Arcadi,
A.; Burini, A.; Cacchi, S.; Delmastro, M.; Marinelli, F.; Pictroni, B. R.
J . Org. Chem. 1992, 57, 976.
(34) (a) Moreau, P.; Neirabeyeh, M. Al.; Guillaumet, G.; Coudert,
G. Tetrahedron Lett. 1991, 32, 5525. (b) Cabiddu, S.; Floris, C.; Melis,
S.; Sotgiu, F.; Cerioni, G. J . Heterocycl. Chem. 1986, 23, 1815. (c) U.
Vogelli, W. Von Phillipsborn, Org. Magn. Reson. 1975, 7, 617. See also
refs 28 and 31a.
(35) Maiti, S.; Mukherjee, M.; Chaudhuri, G.; Helliwell, M.; Kundu,
N. G. Acta Crystallogr. 1999, C55, 1154.

24 J . Org. Chem., Vol. 66, No. 1, 2001
Kundu et al.
Sch em e 5a
romethane. The tosylates could then be very simply
cyclized with CuI in the presence of K2CO3 and tetrabu-
tylammonium bromide in acetonitrile by heating at 80
°C, to the corresponding 3-alkylidene-4-tosyl-3,4-dihydro-
2H-1,4-benzoxazines 34-38 in excellent yields (Table
4).36 Acetonitrile was found to be the best solvent for
cyclization. Attempted cyclization in Et3N, THF, or DMF
yielded poorer results. Also, cyclization with CuI and
Et3N in THF,31 CuI/K2CO3 in CH3CN, NaH in THF, and
NaOEt in EtOH failed. When Pd(OAc)2 (20 mol %) was
used in place of CuI, with K2CO3 (2.5 equiv) and n-Bu4-
NBr (1 equiv) in acetonitrile at 80 °C, cyclization did
occur, but the yields were comparatively lower (about
50%).
3-Alkyliden e-4-t osyl-3,4-dih ydr o-2H -1,4-ben zox-
azines 34-38, in contrast to the regioisomers, e.g.,
2-alkylidene-4-benzyl(alkyl)-3,4-dihydro-2H-1,4-benzox-
azines 9, were found to be stable in chloroform and on
the silica gel column. The structures of the compounds
were established through usual analytical and spectro-
scopic (1H NMR, 13C NMR, IR) methods.The compounds
34-38 were assigned the Z-stereochemistry on the basis
a
Reaction conditions: (i) (PPh3)2PdCl2 (6 mol%, with respect
to 15), CuI (10 mol % with respect to 15) Et3N, rt, 16 h. (ii) KOH
(25 equiv) EtOH/H2O, 80 °C, 8-10 h.
catalysis resulted in the substituted dialkynyl compounds
16 which on cyclization with KOH in EtOH/H2O resulted
in the bis(benzoxazinyl) derivatives 17 in good yields
(Scheme 5 and Table 2).
3
of their J CH values.34 For example compound 34 had the
3J CH value equal to 4.73 Hz. We have also synthesized a
bis-benzo-oxazinyl derivative 39 of 3-alkylidene-4-tosyl-
3,4-dihydro-2H-1,4-benzoxazine starting from compound
21 by using 1,2-diiodobenzene 15a as the aryl iodide (see
Table 4 and Scheme 7) and following the procedures as
described.
Syn th esis of Som e P oten tia lly Biologica lly Active
Com p ou n d s. Through our synthetic protocol, we have
been able to synthesize some pyrimidine ring substituted
benzoxazinederivatives,e.g.,(Z)-4-benzyl-2-[(2,4-dimethoxy-
pyrimidin-5-yl)methylidene]-3,4-dihydro-2H-1,4-benzoxazine,
9g, and (Z)-3-[(2,4-dimethoxypyrimidin-5-yl)methylidene)-
4-tosyl-3,4-dihydro-2H-1,4-benzoxazine, 37. Compound
37 could be demethylated with chlorotrimethylsilane and
sodium iodide in acetonitrile37 to a novel 5-substituted
uracil derivative 40 (Scheme 8).
Similar attempted demethylation of 9g, however, led
to the breakdown of the compound. Hence, 9g was
hydrogenated to the corresponding saturated derivative
18g which was then demethylated to the uracil derivative
41 (Scheme 8). The importance of uracil derivatives as
anticancer and antiviral agents is well established.38 We
believe 40 and 41 could have interesting biological
activities.39
It was noticed that the palladium-catalyzed reactions
of the di-iodo compounds proceeded in modest yields only
due to considerable polymerization of the alkyne 6 taking
place under the reaction conditions. However, the cy-
clization proceeded in better yields (58-84%). The bis-
(benzoxazinyl) derivatives were characterized by their
analytical and spectral data. Particularly, the mass
spectra of the compounds 17, which showed the M+ ions,
confirmed the bis(benzoxazinyl) structures (see Experi-
mental Section).
Syn th esis of 2-Alk yl-3,4-d ih yd r o-2H-1,4-ben zox-
a zin es. We have also extended the scope of this reaction
by synthesizing the 2-alkyl-3,4-dihydro-2H-1,4-benzox-
azines 18 by the hydrogenation of the corresponding (Z)-
4-alkyl-2-alkylidene-3,4-dihydro-2H-1,4-benzoxazines 9
as shown in Scheme 6 and Table 3. The hydrogenation
was carried out with Pd/C as catalyst in excellent yields.
It was observed that the benzyl group on the N-atom
was removed during the hydrogenation procedure. The
hydrogenation products contain the skeleton of many
naturally occurring benzoxazine-containing structures.
Syn th esis of (Z)-3-Alk ylid en e-4-tosyl-3,4-d ih yd r o-
2H-1,4-ben zoxa zin es. We have synthesized the regioi-
somers of compounds 9, e.g., (Z)-3-alkylidene-4-tosyl-3,4-
dihydro-2H-1,4-benzoxazines 34-38 through palladium-
copper-catalyzed reactions as shown in Scheme 7 and
Table 4.
o-Nitrophenol 19 on treatment with propargyl bromide
in the presence of K2CO3 in acetone yielded 2-(prop-2′-
ynyloxy)nitrobenzene 20 which was reduced with iron
powder in acetic acid to 2-(prop-2′-ynyloxy)aniline 21.
Compound 21 underwent C-arylation with aryl iodides
under palladium-copper catalysis in triethylamine to the
disubstituted alkynes 22-26. Interestingly, in contrast
to the case of the O-tosylates 6, the N-tosylate of 21 did
not undergo the arylation reaction. Again, the free
amines 22-26 could not be cyclized to the corresponding
benzoxazines under various conditions, e.g., i. Pd(OAc)2,
LiCl, K2CO3 in DMF, 100 °C, 16 h;32 ii. PdCl2 in CH3CN,
reflux, 24 h; iii. CuI, Et3N in CH3CN, 80 °C, 24 h; iv.
CuI, Bu4NBr, K2CO3 in CH3CN at 80 °C, 24 h. Hence
22-27 were converted to the corresponding tosylates
with tosyl chloride in the presence of pyridine in dichlo-
Con clu sion
Thus, we have described for the first time a highly
successful general method for the synthesis of 2-alkyl-
(36) For other methods of hydroamination of alkynes, see: (a)
through imidozirconium complexes: Baranger, A. M.; Walsh, P. J .;
Bergman, R. G. J . Am. Chem. Soc. 1993, 115, 2753 and references
therein; (b) through imidotitanium complexs: McGrane, P. L.; J ensen,
M.; Livinghouse, T. J . Am. Chem. Soc. 1992, 114, 5459. McGrane, P.
L.; Livinghouse, T. J . Org. Chem. 1992, 57, 1323. McGrane, P. L.;
Livinghouse, T. J . Am. Chem. Soc. 1993, 115, 11485.
(37) Morita, T.; Okamoto, Y.; Sakurai, H. J . Chem. Soc., Chem.
Commun., 1978, 874.
(38) (a) Heidelberger, C. Pyrimidine and Pyrimidine Antimetabolites
in Cancer Medicine; Holland, J . F., Frei, E., Eds.; Lea and Febiger:
Philadelphia, PA, 1984; pp 801-824. (b) De Clercq, E. J . Med. Chem.
1995, 38, 2491. (c) Kundu, N. G.; Das, B.; Spears, C. P.; Majumdar,
A.; Kang, S. I. J . Med. Chem. 1990, 33, 1975. (d) Kundu, N. G.;
Mahanty, J . S.; Chowdhury, C.; Dasgupta, S. K.; Das, B.; Spears, C.
P.; Balzarini, J .; De Clercq, E. Eur. J . Med. Chem. 1999, 34, 389 and
refeences cited therein.
(39) The biological (anticancer and antiviral) studies on these
compounds are in progress.

Palladium-Catalyzed Heteroannulation
J . Org. Chem., Vol. 66, No. 1, 2001 25
Ta ble 2. Syn th esis of Bis(ben zoxa zin yl) Der iva tives (Sch em e 5)
a
b
Yields are of chromatographically pure material and based on compound 15. Yields of chromatographically pure materials are based
on 16.
Sch em e 6
Sch em e 7a
Ta ble 3. Hyd r ogen a tion of (Z)-N-Ar yl(a lk yl)-2-
a lk ylid en e-3,4-d ih yd r o-2H-1,4-ben zoxa zin es (Sch em e 6)a
starting
entry materials 9
yields
(%)
products 18 (Ar, R)
18a (C6H5, H)
18b (3-ClC6H4, H)
18d (4-MeC6H4, H)
18e (1-naphthyl, H)
1
2
3
4
5
6
9a
9b
9d
9e
9g
9h
81
86
81
83
18g (2,4-dimethoxy-5-pyrimidinyl, H) 85
18h (C6H5, Me) 82
a
Hydrogenation was carried out by treatment of compound 9
a
(0.20 mmol) in dry ethyl acetate (9 mL) with hydrogen at room
temperature under atmospheric pressure with Pd-C (10%) as
catalyst. Yields refer to chromatographically isolated pure prod-
ucts.
Reaction conditions: (i) propargyl bromide (1.2 equiv, 43.08
mmol), K2CO3 (35.9 mmol), in acetone (40 mL), reflux, 16 h. (ii)
Fe in AcOH. (iii) ArI (0.83 equiv, 2.03 mmol), (PPh3)2PdCl2 (0.06
mmol), CuI (0.1 mmol), Et3N (12 mL). (iv) Tosyl chloride (1 equiv,
1.3 mmol), Py (1.3 mmol), CH2Cl2 (9 mL), rt, 2 h. (v) CuI (20 mol
%), K2CO3 (2.5 equiv), Bu4NBr (1 equiv), CH3CN (11 mL), 12 h,
80 °C.
idene- and 3-alkylidene-3,4-dihydro-2H-benzo-1,4-ox-
azines through palladium-copper-catalyzed reactions.
The method is characterized by the use of readily
available inexpensive starting materials, nonhazardous
reagents, mild reaction conditions, and relatively good
to excellent yields of products. The method is also highly
regio- and stereoselective in nature. Thus the process is
amenable for the synthesis of a large number of 2- and
3-substituted benzoxazines, bis-benzoxazines, and vari-
ous potentially biologically active compounds containing
the benzoxazine structure.

26 J . Org. Chem., Vol. 66, No. 1, 2001
Kundu et al.
Ta ble 4. Syn th esis of (Z)-3-Alk yl(a r yl)id en e-4-tosyl-3,4-d ih yd r o-2H-1,4-ben zoxa zin es (34-38) a n d a Bis-ben zoxa zin yl
Der iva tive (39) fr om 2-(P r op -2′-yn yloxy)a n ilin e 21 (Sch em e 7)
aryl iodides
(ArI) 7, Ar
disubstituted
tosylates
3-alkyl(aryl)idene benzoxazines 34-38
and bis-benzoxazinyl derivative 39 (%)c
entry
alkynes 22-27 (%)a
28-33 (%)b
1
2
3
4
C6H5, 7a
3-ClC6H4, 7b
22 (78)
23 (77)
24 (70)
25 (78)
28 (72)
29 (82)
30 (80)
31 (73)
34 (88)
35 (86)
36 (82)
37 (71)
4-MeC6H4, 7d
2,4-dimethoxy-
5-pyrimidinyl, 7g
4-MeOC6H4, 7i
2-IC6H4, 15a
5
6
26 (65)
27 (56)
32 (68)
33 (61)
38 (69)
39 (38)
a
b
The yields refer to chromatographically isolated pure materials and based on compound 7. Yields of tosylates are based on
corresponding disubstituted alkynes. c Yields of benzoxazines and bis-benzoxazine are based on corresponding tosylates.
Calcd for C16H15NSO3: C, 63.76; H, 5.01; N, 4.64. Found: C,
63.67; H, 4.91; N, 4.72.
Sch em e 8
2-(N-Ben zyl-N-p r op -2′-yn yla m in o)p h en yl p-Tolu en e-
su lfon a te (6a ). A mixture of 2-(N-prop-2′-ynylamino)phenyl
p-toluenesulfonate 5 (2 g, 6.63 mmol) and anhydrous K2CO3
(920 mg, 6.63 mmol) in dry DMF (15 mL) was stirred for 16 h
at room temperature under nitrogen atmosphere. Benzyl
bromide (1.7 g, 9.94 mmol) in DMF (5 mL) was then added
slowly during 10 min. The whole mixture was heated at 80 °C
for 48h with constant stirring under nitrogen atmosphere. The
residue obtained after removal of DMF under reduced pressure
was extracted with chloroform (3 × 30 mL) and water (50 mL).
The combined chloroform layer was washed with water (2 ×
50 mL) and dried over anhydrous sodium sulfate. After
removal of solvent, the residue was purified by column
chromatography over silica gel using chloroform as eluent.
2-(N-Benzyl-N-prop-2′-ynylamino)phenyl p-toluenesulfonate
6a was obtained as a colorless oil (1.6 g, 62%). IR (liquid film)
3290, 1600 cm-1; 1H NMR (60 MHz, CCl4) δ 2.16 (t, 1H), 2.36
(s, 3H), 3.60 (d, J ) 3.0 Hz, 2H), 4.30 (s, 2H), 6.51-7.24 (m,
11H), 7.66-7.81 (m, 2H). Anal. Calcd for C23H21NSO3: C, 70.56;
H, 5.40; N, 3.57. Found: C, 70.43; H, 5.16; N, 3.36.
Exp er im en ta l Section
Melting points are uncorrected. Reactions were performed
in an argon or nitrogen atmosphere. Bis(triphenylphosphine)-
palladium(II) chloride was obtained from Aldrich Chemical Co,
Milwaukee, WI. Petroleum ether used was the fraction boiling
between 60 and 80 °C, and distilled ether refers to diethyl
ether. Column chromatography was done on neutral alumina
and silica gel. TLC was performed on 60F-254 precoated
sheets. Aryl iodides (7b, 7c, etc.) were prepared according to
the procedure given for the synthesis of iodobenzene.40 2-Io-
dothiophene,41 2,5-diiodothiophene,41 and 5-iodo-2,4-dimethoxy-
pyrimidine42 were synthesized according to known procedures.
1H NMR in CDCl3 solutions were recorded at 300 MHz and
that of CCl4 solutions at 60 MHz. 13C NMR spectra were
For the preparation of N-methyl and N-ethyl derivatives,
6b and 6c, respectively, the same procedure was used with
methyl iodide or ethyl iodide instead of benzyl bromide.
2-(N-Met h yl-N-p r op -2′-yn yla m in o)p h en yl p -t olu en e-
su lfon a te (6b): yield 83%; mp 55-56 °C; IR 3280, 1598 cm-1
;
1H NMR (60 MHz, CCl4) δ 2.00 (t, 1H), 2.30 (s, 3H), 2.36 (s,
3H), 3.54 (d, J ) 3.0 Hz, 2H), 6.66-7.24 (m, 6H), 7.51-7.66
(m, 2H). Anal. Calcd for C17H17NSO3: C, 64.73; H, 5.43; N, 4.44.
Found: C, 64.47; H, 5.30; N, 4.18.
2-(N-Eth yl-N-p r op -2′-yn yla m in o)p h en yl p-tolu en esu l-
fon a te (6c): yield 71%; mp 65 °C; IR 3285, 1600 cm-1; 1H NMR
(60 MHz, CCl4) δ 1.0 (t, 3H), 2.03 (t, 1H), 2.39 (s, 3H), 3.03 (q,
2H), 3.6 (d, J ) 2.0 Hz, 2H), 6.9-7.26 (m, 6H), 7.56-7.66 (m,
2H). Anal. Calcd for C18H19NSO3: C, 65.62; H, 5.81; N, 4.25.
Found: C, 65.35; H, 5.77; N, 4.20.
3
recorded at 75 MHz. J CH values were obtained, performing
13C NMR experiments under proton-coupled mode.
2-(N-P r op-2′-yn ylam in o)ph en yl p-Tolu en esu lfon ate (5).
A mixture of 2-aminophenyl p-toluenesulfonate30 4 (5 g, 19.0
mmol) and anhydrous potassium carbonate (2.62 g, 19.0 mmol)
in dry DMF (30 mL) was stirred at room temperature for about
16 h under nitrogen atmosphere. Propargyl bromide (2.71 g,
22.8 mmol) in dry DMF (5 mL) was then added slowly during
15 min. The mixture was heated at 80 °C for 48 h with
constant stirring under nitrogen atmosphere. DMF was re-
moved from the reaction mixture under reduced pressure, and
the residue was extracted with chloroform (3 × 40 mL) and
distilled water (50 mL). The chloroform extract was washed
with water (2 × 50 mL) and dried over anhydrous sodium
sulfate. After removal of solvent, the residue was purified by
column chromatography over silica gel using 1:1 chloroform-
light petroleum ether as eluent to yield 2-(N-prop-2′-ynylami-
no)phenyl p-toluenesulfonate 5 as a colorless solid (3.3 g, 58%).
The product was finally crystallized from petroleum ether, mp
105-107 °C; IR 3402, 3286 cm-1; 1H NMR (300 MHz, CDCl3)
δ 2.18 (t, 1H), 2.45 (s, 3H), 3.80 (d, J ) 3.0 Hz, 2H), 4.28 (s,
1H, br), 6.61-6.66 (m, 1H), 6.72 (d, J ) 9.0 Hz, 1H), 6.89 (d,
J ) 9.0 Hz, 1H), 7.13 (m, 1H), 7.31 (m, 2H), 7.76 (m, 2H). Anal.
Typ ica l P r oced u r e for th e Syn th esis of 2-[N-Ben zyl-
N-(3′-p h en ylp r op -2′-yn yl)a m in o]p h en yl p -Tolu en esu l-
fon a te 8a . A mixture of iodobenzene 7a (360 mg, 1.76 mmol),
(PPh3)2PdCl2 (35 mg, 0.05 mmol), and CuI (17 mg, 0.09 mmol)
was stirred in triethylamine (9 mL) for 20 min under N2
atmosphere. The acetylenic compound 6a (830 mg, 2.11 mmol)
in Et3N (3 mL) was added very slowly, and the whole reaction
mixture was stirred at room temperature for about 16 h. After
removal of solvent under reduced pressure, the reaction
mixture was poured in water (100 mL) and extracted with
chloroform (3 × 50 mL). The combined chloroform layer was
washed with water and dried over anhydrous Na2SO4. After
the removal of solvent, the residue was chromatographed over
silica gel, eluent being chloroform/petroleum ether (75/25, V/V),
affording compound 8a (760 mg, 92%) as a colorless oil; IR
(liquid film) 2210, 1597 cm-1
;
1H NMR (300 MHz, CDCl3) δ
2.38 (s, 3H), 3.69 (s, 2H), 4.26 (s, 2H), 7.01-7.02 (m, 1H), 7.19-
7.39 (m, 15H), 7.75 (d, J ) 8.1 Hz, 2H). Anal. Calcd for C29H25
-
NSO3: C, 74.49; H, 5.38; N, 2.99. Found: C, 74.14; H, 5.42; N,
(40) Vogel, A. I. A Text Book of Practical Organic Chemistry, 4th
ed.; ELBS, Longman Group Limited: London, 1978; p 695.
(41) Barker, J . M.; Huddleston, P. R.; Wood, M. L. Synth. Commun.
1975, 5, 59.
2.72.
Similar reaction conditions were used for compounds 8b-
k .
(42) Das, B.; Kundu, N. G. Synth. Commun. 1988, 855.
2-[N-Ben zyl-N-{3′-(3-ch lor oph en yl)pr op-2′-yn yl}am in o]-

Palladium-Catalyzed Heteroannulation
J . Org. Chem., Vol. 66, No. 1, 2001 27
p h en yl p-tolu en esu lfon a te (8b): IR (liquid film) 2220, 1596
116.2, 119.6, 122.5, 123.9, 125.4, 125.5, 125.7, 126.8, 127.2,
127.5, 127.7, 128.6, 128.7, 130.8, 131.3, 133.6, 136.1, 137.2,
143.6, 146.2; 13C NMR (75 MHz, CDCl3, DEPT 135) δ 50.0
(inverted), 55.0 (inverted), 101.1, 114.2, 116.4, 119.8, 122.7,
124.2, 125.6, 125.7, 125.9, 127.0, 127.4, 127.7, 128.0, 128.8,
128.9. Anal. Calcd for C26H21NO: C, 85.91; H, 5.82; N, 3.85.
Found: C, 85.82, H, 6.02; N, 3.74.
1
cm-1; H NMR (300 MHz, CDCl3) δ 2.27 (s, 3H), 3.64 (s, 2H),
4.15 (s, 2H), 6.89-6.93 (m, 1H), 7.06-7.30 (m, 14H), 7.65 (d,
J ) 9 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 20.6, 40.0, 55.6,
83.4, 85.1, 121.6, 122.2, 122.5, 123.7, 126.4, 126.5, 127.3, 127.4,
127.4, 128.2, 128.4, 128.5, 128.7, 130.4, 132.3, 133.0, 136.0,
142.2, 142.9, 144.0; 13C NMR (75 MHz, CDCl3, DEPT 135) δ
21.8, 41.2 (inverted), 55.8 (inverted), 122.9, 123.4, 123.7, 127.6,
127.7, 128.5, 128.6, 129.4, 129.6, 129.7, 130.0, 131.6. Anal.
Calcd for C29H24NSO3Cl: C, 69.38; H, 4.81; N, 2.79. Found: C,
69.03; H, 4.42; N, 2.30.
2-[N-Ben zyl-N-{3′-(4-m eth ylph en yl)pr op-2′-yn yl}am in o]-
p h en yl p-tolu en esu lfon a te (8d ): mp 118-119 °C; IR 2230,
1598 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 2.37 (s,
3H), 3.68 (s, 2H), 4.26 (s, 2H), 6.98-7.39 (m, 15H), 7.73-7.76
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 21.9, 22.0, 41.5, 56.0,
84.4, 86.4, 120.4, 123.2, 123.7, 123.8, 127.8, 127.9, 128.7, 128.9,
129.5, 129.8, 129.8, 131.9, 133.8, 137.6, 138.7, 143.6, 144.5,
145.4; 13C NMR (75 MHz, CDCl3, DEPT 135) δ 21.6, 21.8, 41.2
(inverted), 55.7 (inverted), 122.9, 123.4, 123.5, 127.5, 127.6,
(Z)-4-Ben zyl-2-[(2-t h ien yl)m et h ylid en e]-3,4-d ih yd r o-
2H-1,4-ben zoxa zin e (9f): mp 99-101 °C; IR 1680, 1600 cm-1
;
1H NMR (300 MHz, CDCl3) δ 3.66 (s, 2H), 4.35 (s, 2H), 5.71
(s, 1H), 6.81-7.04 (m, 6H), 7.16-7.35 (m, 6H); 13C NMR (75
MHz, CDCl3) δ 48.7 (3J CH ) 4.18 Hz), 54.7, 99.5, 113.9, 116.2,
119.6, 122.7, 124.8, 125.3, 126.3, 127.4, 127.7, 128.7, 135.8,
137.1, 137.4, 143.4, 143.5; 13C NMR (75 MHz, CDCl3, DEPT
135) δ 48.9 (inverted) 54.9 (inverted), 99.7, 114.2, 116.4, 119.8,
122.9, 125.0, 125.5, 126.5, 127.6, 127.9, 128.9. Anal. Calcd for
C20H17NSO: C, 75.20; H, 5.36; N, 4.38. Found: C, 75.20; H, 5.47;
N, 4.24.
(Z)-4-Ben zyl-2-[(2,4-d im et h oxyp yr im id in -5-yl)m et h -
ylid en e]-3,4-d ih yd r o-2H-1,4-ben zoxa zin e (9g): mp 130-
132 °C; IR 1680, 1600 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.71
(s, 2H), 4.39 (s, 2H), 4.40 (s, 3H), 4.42 (s, 3H), 5.46 (s, 1H),
6.78-6.91 (m, 3H), 7.05-7.08 (m, 1H), 7.26-7.37 (m, 5H), 9.06
(s, 1H). Anal. Calcd for C22H21N3O3: C, 70.38; H, 5.63; N, 11.19.
Found: C, 70.01; H, 5.98; N, 11.01.
128.4, 128.6, 129.2, 129.5, 129.5, 131.6. Anal. Calcd for C30H27
-
NSO3: C, 74.81; H, 5.65; N, 2.90. Found: C, 74.86; H, 5.74; N,
2.85.
2-[N-Ben zyl-N-{3′-(2-th ien yl)p r op -2′-yn yl}]a m in op h en -
yl p-tolu en esu lfon a te (8f): IR (liquid film) 2240, 1598 cm-1
;
1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 3.72 (s, 2H), 4.24
(s, 2H), 6.94-6.95 (m, 2H), 7.12-7.38 (m, 12H), 7.74 (d, J )
9.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 21.6, 41.2, 55.6, 88.8,
122.7, 122.9, 123.2, 123.5, 126.7, 126.9, 127.4, 127.5, 128.3,
128.4, 129.2, 129.4, 131.7, 133.3, 137.0, 143.1, 143.9, 145.0;
13C NMR (75 MHz, CDCl3, DEPT 135) δ 21.8, 41.4 (inverted),
55.8 (inverted), 122.9, 123.4, 123.7, 126.9, 127.1, 127.6, 127.7,
128.5, 128.6, 129.5, 129.6, 131.9. Anal. Calcd for C27H23NS2O3:
C, 68.32; H, 5.09; N, 2.95. Found: C, 68.08; H, 4.93; N, 2.83.
Typ ica l P r oced u r e for th e Syn th esis of (Z)-4-Ben zyl-
2-ben zylid en e-3,4-d ih yd r o-2H-1,4-ben zoxa zin e 9a . The
disubstituted alkyne 8a (670 mg, 1.42 mmol) was refluxed with
KOH/H2O (1.5 g, 26.8 mmol/3 mL) in ethanol (20 mL) for 8 h
under Ar atmosphere. It was then cooled to room temperature
and neutralized with glacial acetic acid, and after the removal
of solvent the residue was worked up with diethyl ether (100
mL) and water (2 × 50 mL). The ether layer was dried over
anhydrous Na2SO4. After the removal of solvent, the residue
was chromatographed over neutral alumina eluting with
petroleum ether/diethyl ether (80/20, V/V), affording compound
9a (415 mg, 93%) as a colorless solid. The product was finally
crystallized from petroleum ether/diethyl ether, mp 57-59 °C;
IR 1680, 1600 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.71 (s, 2H),
4.41 (s, 2H), 5.39 (s, 1H), 6.84-6.96 (m, 3H), 7.16-7.42 (m,
9H), 7.73-7.76 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 49.7 (3J CH
) 4.3 Hz), 54.7, 104.7, 114.0, 116.2, 119.6, 122.6, 126.2, 127.7,
128.3, 128.5, 128.7, 135.1, 136.1, 137.2, 143.6, 145.6; 13C NMR
(75 MHz, CDCl3, DEPT 135) δ 49.9 (inverted), 54.9 (inverted),
104.9, 114.2, 116.4, 119.8, 122.8, 126.4, 127.6, 127.9, 128.5,
128.7, 128.9. Anal. Calcd for C22H19NO: C, 84.31; H, 6.11; N,
4.47. Found: C, 84.18; H, 6.24; N, 4.34.
(Z)-4-Meth yl-2-ben zylid en e-3,4-d ih yd r o-2H-1,4-ben zox-
1
a zin e (9h ): colorless oil; IR (liquid film) 1680, 1600 cm-1; H
NMR (300 MHz, CDCl3) δ 2.88 (s, 3H), 3.67 (s, 2H), 5.45 (s,
1H), 6.74-6.77 (m, 2H), 6.81-6.84 (m, 1H), 6.94-6.97 (m, 1H),
7.06-7.36 (m, 4H), 7.68 (d, J ) 7.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 38.2, 52.5, 104.6, 112.9, 115.8, 119.5, 122.6, 126.1,
128.2, 128.5, 128.5, 129.9, 135.1, 136.9, 143.4, 145.8; 13C NMR
(75 MHz, CDCl3, DEPT 135) δ 38.4, 52.7 (inverted), 104.8,
113.1, 116.0, 119.7, 122.8, 126.3, 128.4, 128.7, 130.2. Anal.
Calcd for C16H15NO: C, 80.98; H, 6.37; N, 5.90. Found: C, 80.70;
H, 6.45; N, 5.88.
(Z)-4-Eth yl-[(3-ch lor oph en yl)m eth yliden e]-3,4-dih ydr o-
2H-1,4-ben zoxa zin e (9k ): colorless oil; IR (liquid film) 1680,
1600 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.16 (t, 3H), 3.30 (q,
2H), 3.66 (s, 2H), 5.34 (s, 1H), 6.74-6.91 (m, 3H), 7.04-7.23
(m, 3H), 7.49 (d, J ) 7.8 Hz, 1H), 7.67 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 10.3, 44.4, 48.7, 103.1, 113.3, 116.1, 119.0,
122.8, 125.9, 126.4, 128.2, 129.4, 134.0, 135.3, 137.0, 143.3,
146.9; 13C NMR (75 MHz, CDCl3, DEPT 135) δ 10.6, 44.6
(inverted), 48.9 (inverted), 103.3, 113.5, 116.3, 119.2, 123.0,
126.2, 126.6, 128.4, 129.6. Anal. Calcd for C17H16NOCl: C,
71.44; H, 5.64; N, 4.90. Found: C, 71.26; H, 5.58; N, 4.87.
Syn th esis of 4-Meth yl-2-m eth ylen e-3,4-d ih yd r o-2H-1,4-
ben zoxa zin e (10). The monosubstituted alkyne 6b (300 mg,
0.95 mmol) was refluxed with KOH/H2O (18.05 mmol/1.5 mL)
in ethanol (10 mL) for 8 h under Ar atmosphere. It was cooled
to room temperature and neutralized with glacial acetic acid,
and after the removal of solvent the residue was worked up
with diethyl ether (50 mL) and water (2 × 20 mL). The ether
layer was dried over anhydrous Na2SO4. After the removal of
solvent, the residue was chromatographed over neutral alu-
mina eluting with petroleum ether/diethyl ether (90/10, V/V),
affording compound 10 (140 mg, 91%) as a colorless oil; IR
Similar reaction conditions were used for the synthesis of
compounds 9b-k .
1
(Z)-4-Ben zyl-2-[(4-m eth ylp h en yl)m eth ylid en e]-3,4-d i-
h yd r o-2H-1,4-ben zoxa zin e (9d ): mp 114-116 °C; IR 1680,
1600 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.34 (s, 3H), 3.65 (s,
2H), 4.37 (s, 2H), 5.32 (s, 1H), 6.78-6.92 (m, 3H), 7.09-7.15
(m, 3H), 7.24-7.36 (m, 5H), 7.57 (d, J ) 8.1 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 21.2, 49.7 (3J CH ) 3.65 Hz), 54.8, 104.7,
114.0, 116.1, 119.6, 122.5, 127.4, 127.7, 128.4, 128.7, 129.0,
132.3, 135.8, 136.1, 137.3, 143.7, 144.8; 13C NMR (75 MHz,
CDCl3, DEPT 135) δ 21.4, 49.9 (inverted), 55.0 (inverted),
104.9, 114.2, 116.3, 119.8, 122.7, 127.6, 127.9, 128.6, 128.9,
129.2. Anal. Calcd for C23H21NO: C, 84.36; H, 6.46; N, 4.27.
Found: C, 84.21; H, 6.68; N, 4.31.
(liquid film) 1680, 1600 cm-1; H NMR (60 MHz, CCl4) δ 2.8
(s, 3H), 3.70 (s, 2H), 4.10 (s, 1H), 4.8 (s, 1H), 6.9-7.2 (m,4H).
Anal. Calcd for C10H11NO: C, 74.5; H, 6.87; N, 8.69. Found: C,
74.25; H, 6.62; N, 8.57.
Syn t h esis of (Z)-2-Ben zylid en e-3,4-d ih yd r o-2H -1,4-
ben zoxa zin e (14). A mixture of iodobenzene 7a (150 mg, 0.73
mmol), (PPh3)2PdCl2 (15 mg, 0.02 mmol), and CuI (7 mg, 0.04
mmol) in triethylamine (9 mL) was stirred under argon
atmosphere for 15 min. Then compound 5 (264 mg, 0.87 mmol)
in Et3N (3 mL) was added very slowly. The resulting solution
was stirred at room temperature for about 16 h under N2
atmosphere. After usual workup with chloroform-water and
purification by chromatography on silica gel with chloroform-
petroleum ether (75/25, V/V) as eluent, the disubstituted
alkyne 11 was obtained as an oil, which was hydrolyzed with
aqueous ethanolic solution of KOH at 80 °C for about 8-10 h
to yield 13. Compound 13 (540 mg, 2.41 mmol) was stirred
(Z)-4-Ben zyl-2-[(2-r-n aph th yl)m eth yliden e]-3,4-dih ydr o-
2H-1,4-ben zoxa zin e (9e): mp 117-119 °C; IR 1660, 1600
1
cm-1; H NMR (300 MHz, CDCl3) δ 3.84 (s, 2H), 4.62 (s, 2H),
6.03 (s, 1H), 6.82-7.06 (m, 4H), 7.38-7.57 (m, 8H), 7.76-8.44
(m, 4H); 13C NMR (75 MHz, CDCl3) δ 49.8; 54.8, 100.9, 114.0,

28 J . Org. Chem., Vol. 66, No. 1, 2001
Kundu et al.
with the mixture of Pd(OAc)2 (5 mol %, 0.12 mmol), LiCl (1.21
mmol), and K2CO3 (6.02 mmol) at 100 °C in DMF for 16 h
under argon atmosphere. After usual workup with ether-
water, and purification by chromatography on neutral alu-
mina, ether-petroleum ether (20/80, V/V) as eluent, product
14 was obtained in 15% yield. The product 14 could also be
obtained by hydrolyzing 5 to compound 12, which was then
subsequently arylated and then cyclized with Pd(OAc)2, LiCl,
and K2CO3 in DMF at 100 °C for 16 h; mp 116-118 °C; IR
J 1 ) 15.0 Hz, J 2 ) 6.0 Hz, 1H), 3.09-3.19 (m, 2H), 3.24 (dd,
J 1 ) 11.7 Hz, J 2 ) 2.7 Hz, 1H), 4.34 (m, 2H), 6.59-6.66 (m,
2H), 6.75-6.85 (m, 2H), 7.20-7.33 (m, 5H). Anal. Calcd for
15H15NO: C, 79.96; H, 6.71; N, 6.21. Found: C, 79.81; H, 6.52;
N, 6.09.
Similarly, compounds 18b,d ,e,g,h were synthesized through
C
hydrogenation of the corresponding unsaturated analogues
9b,d ,e,g,h , respectively.
2-[(3-C h lo r o p h e n y l)m e t h y l]-3,4-d i h y d r o -2H -1,4-
ben zoxa zin e(18b): colorless oil; IR (liquid film) 3390, 2918,
1
3390, 1680, 1600 cm-1; H NMR (300 MHz, CDCl3) δ 3.96 (s,
1
1608 cm-1; H NMR (300 MHz, CDCl3) δ 2.84 (dd, J 1 ) 14.1
2H), 5.53 (s, 1H), 6.75-6.93 (m, 3H), 7.12-7.45 (m, 5H), 7.73-
7.80 (m, 2H). Anal. Calcd for C15H13NO: C, 80.69; H, 5.86; N,
6.27. Found: C, 80.65; H, 5.80; N, 6.18.
Hz, J 2 ) 6.9 Hz, 1H), 3.03-3.13 (m, 2H), 3.30 (dd, J 1 ) 11.4
Hz, J 2 ) 2.7 Hz, 1H), 4.31 (m, 1H), 6.57-6.60 (m, 1H), 6.66-
6.69 (m, 1H), 6.74-6.81 (m, 2H), 7.14-7.26 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 38.7; 44.3, 74.2, 115.3, 116.8, 118.9, 121.2,
126.7, 127.5, 129.4, 129.6, 133.0, 134.1, 139.3, 143.4. 13C NMR
(75 MHz, CDCl3, DEPT 135) δ 38.9 (inverted), 44.5 (inverted),
74.4, 115.5, 117.0, 119.1, 121.4, 126.9, 127.8, 129.6, 129.8.
Anal. Calcd for C15H14NOCl: C, 69.36; H, 5.43; N, 5.39. Found:
C, 69.17; H, 5.31; N, 5.26.
Syn th esis of Su bstitu ted Dia lk yn es 16a , 16b, 16c. The
substituted dialkynes (16a -c) were synthesized following the
same procedure as for the disubstituted alkynes (8a -k ) using
di-iodo aryl compounds (15) instead of the aryl iodides (7).
(16a ): mp 118-120 °C; IR 2225, 1600 cm-1 1H NMR (60
;
MHz, CCl4) δ 2.35 (s, 6H), 3.61 (s, 4H), 4.18 (s, 4H), 6.78-
7.45 (m, 18H), 7.46-7.78 (m, 12H). Anal. Calcd for C52H44N2S2O6:
C, 72.87; H, 5.17; N, 3.26. Found: C, 72.66; H, 4.99; N, 2.98.
(16b): mp 97-98 °C; IR 2230, 1598 cm-1; 1H NMR (60 MHz,
CCl4) δ 2.36 (s, 6H), 2.48 (s, 6H), 3.75 (s, 4H), 6.75-7.24 (m,
14H), 7.48-7.66 (m, 4H). Anal. Calcd for C38H34N2S3O6: C,
64.20; H, 4.28; N, 3.94. Found: C, 64.06; H, 4.61; N, 3.80.
2-[(4-Met h ylp h en yl)m et h yl]-3,4-d ih yd r o-2H -1,4-b en -
zoxa zin e (18d ): colorless oil; IR (liquid film) 3388, 2918, 1608
cm-1; 1H NMR (300 MHz, CDCl3) δ 2.26 (s, 3H), 2.74 (dd, J 1
12.0 Hz, J 2 ) 6.0 Hz, 1H), 2.99-3.07 (m, 2H), 3.22 (dd, J 1
)
)
12.0 Hz, J 2 ) 3.0 Hz, 1H), 4.19-4.26 (m, 1H), 6.50-6.75 (m,
4H), 7.06-7.09 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 21.5,
39.3, 44.8, 75.2, 115.7, 117.3, 119.3, 121.5, 129.6, 129.7, 133.7,
134.6, 136.5, 144.1; 13C NMR (75 MHz, CDCl3, DEPT 135) δ
20.0, 37.8 (inverted), 43.4 (inverted), 73.8, 114.3, 115.8, 117.9,
120.1, 128.1, 128.3. Anal. Calcd for C16H17NO: C, 80.33; H,
7.11; N, 5.85. Found: C, 80.08; H, 7.01; N, 6.69.
(16c): mp 109-110 °C; IR 2225, 1600 cm-1 1H NMR (60
;
MHz, CCl4) δ 2.30 (s, 6H), 2.39 (s, 6H), 3.72 (s, 4H), 6.84-
7.36 (m, 12H), 7.48-7.69 (m, 8H). Anal. Calcd for C40H36N2S2O6:
C, 68.15; H, 5.14; N, 3.97. Found: C, 67.92; H, 4.95; N, 3.80.
Syn th esis of Bis(ben zoxa zin yl) Der iva tives 17a-c. Bis-
(benzoxazinyl) derivatives (17a -c) were synthesized following
similar reaction conditions as described for the synthesis of
compound 9 from 8. The only difference was that, in case of
compounds 17a -c, workup was done with ethyl acetate-water
instead of diethyl ether-water in order to overcome solubility
problem, and also the products were purified by chromatog-
raphy over neutral alumina, eluent being petroleum ether-
ethyl acetate (80/20, V/V). Crystallization was done with
petroleum ether-ethyl acetate.
2-(P r op -2′-yn yloxy)n itr oben zen e (20). A mixture of 2-ni-
trophenol (5.0 g, 35.9 mmol) and anhydrous K2CO3 (7.45 g,
35.9 mmol) in dry acetone (30 mL) was stirred for 2 h at room
temperature. Propargyl bromide (5.12 g, 43.08 mmol) in dry
acetone (10 mL) was then added during 20 min. The whole
mixture was then heated under reflux for 16 h with constant
stirring under nitrogen atmosphere. Acetone was removed
from the mixture, and the residue was poured in distilled
water (100 mL) and extracted with chloroform (3 × 50 mL).
The combined organic layer was washed with water (100 mL)
and dried over anhydrous Na2SO4. After removal of solvent,
the residue was purified through column chromatography over
silica gel using chloroform-petroleum ether (1:1) as eluent.
Finally the product was crystallized from petroleum ether-
chloroform. A colorless white crystalline solid (4.8 g, 76%); mp
1,2-Bis[(Z)-4′-ben zyl-2′-m eth ylid en e-3′,4′-d ih yd r o-2′H-
1′,4′-ben zoxa zin yl]ben zen e (17a ): mp 132-134 °C; IR 1680,
1600 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.65 (s, 4H), 4.37 (s,
4H), 5.47 (s, 2H), 6.78-6.88 (m, 6H), 6.99-7.02 (m, 2H), 7.22-
7.36 (m, 12H), 7.90 (dd, J 1 ) 5.70 Hz, J 2 ) 3.3 Hz, 2H), MS
m/e (rel inten) 548 (M+, 15). Anal. Calcd for C38H32N2O2: C,
83.18; H, 5.87; N, 5.10. Found: C, 83.15; H, 5.86; N, 5.02.
2,5-Bis[(Z)-4′-m eth yl-2′-m eth ylid en e-3′,4′-d ih yd r o-2′H-
1′,4′-ben zoxa zin yl]th iop h en e (17b): mp 151-152 °C; IR
1
77-78 °C; IR 3300,1600 cm-1; H NMR (60 Mz, CCl4) δ 2.49
(t, 1H), 4.46 (d, J ) 2 Hz, 2H), 6.85-7.82 (m, 4H). Anal. Calcd
for C9H7NO3: C, 61.01; H, 3.98; N, 7.90. Found: C, 61.17; H,
3.83; N, 7.74.
1
1674, 1606 cm-1; H NMR (300 MHz, CDCl3) δ 2.87 (s, 6H),
3.69 (s, 4H), 5.78 (s, 2H), 6.75-6.78 (m, 2H), 6.85-6.88 (m,
2H), 6.95-6.97 (m, 4H), 7.18-7.21 (m, 2H); MS m/e (rel inten)
402 (M+,100). Anal. Calcd for C24H22N2SO2: C, 71.61; H, 5.51;
N, 6.96. Found: C, 71.72; H, 5.41; N, 6.86.
2-(P r op -2′-yn yloxy)a n ilin e (21). It was prepared by the
reduction of compound 20 with Fe/AcOH following the usual
procedure.43
Compound 21 was obtained as colorless oil; IR (liquid film)
3466, 3375, 1604 cm-1; 1H NMR (60 MHz, CCl4) δ 2.4 (t, 1H),
3.5 (s, 2H), 4.56 (d, J ) 2.0 Hz, 2H), 6.4-6.9 (m, 4H). Anal.
Calcd for C9H9NO: C, 73.41; H, 6.16; N, 9.55. Found: C, 73.29;
H, 6.05; N, 9.40.
Typ ica l P r oced u r e for th e Syn th esis of Com p ou n d 22.
A mixture of iodobenzene (415 mg, 2.03 mmol), (PPh3)2PdCl2
(42 mg, 0.06 mmol), and CuI (20 mg, 0.10 mmol) in triethyl-
amine (9 mL) was stirred under N2 atmosphere for 20 min.
Then 2-(prop-2′-ynyloxy)aniline (21) (360 mg, 2.44 mmol) in
triethylamine (3 mL) was added very slowly. The resulting
reaction mixture was stirred at room temperature for 16 h
under N2 atmosphere. After the removal of triethylamine, the
reaction mixture was poured in water (50 mL) and extracted
with chloroform (3 × 40 mL). The combined chloroform layer
was washed with water and dried over anhydrous Na2SO4.
After the removal of solvent, the residue was chromatographed
over silica gel using chloroform/petroleum ether (75/25,V/V)
1,4-Bis[(Z)-4′-m eth yl-2′-m eth ylid en e-3′,4′-d ih yd r o-2′H-
1′,4′-ben zoxa zin yl]ben zen e (17c): mp 186-187 °C; IR 1672,
1605 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.87 (s, 6H), 3.67 (s,
4H), 5.44 (s, 2H), 6.74-6.85 (m, 4H), 6.94-6.96 (m, 2H), 7.13
(dd, J 1 ) 7.7 Hz, J 2 ) 1.4 Hz, 2H), 7.66 (s, 4H); 13C NMR (75
MHz, CDCl3) δ 38.7, 53.0, 105.1, 113.4, 116.3, 119.9, 123.0,
128.9, 133.5, 137.4, 143.9, 146.0; 13C NMR (75 MHz, CDCl3,
DEPT 135) δ 38.4, 52.7 (inverted), 104.8, 113.1, 116.0, 119.6,
122.7, 128.6; MS m/e (rel inten) 396 (M+, 50). Anal. Calcd for
C
26H24N2O2: C, 78.76; H, 6.10; N, 7.06. Found: C, 78.89; H,
5.94; N, 6.79.
Typ ica l P r oced u r e for th e Syn th esis of 2-Ben zyl-3,4-
d ih yd r o-2H -1,4-b en zoxa zin e (18a ). Compound 9a (100
mg,0.32 mmol) was hydrogenated in the presence of 10% Pd/C
catalyst in dry ethyl acetate (9 mL) under atmospheric
pressure. After 24 h, the catalyst was removed by filtration
and washed with ethyl acetate (3 mL). The combined filtrate
was evaporated to dryness to give a gummy material which
was purified by column chromatography over neutral alumina
with petroleumether/diethyl ether (80/20,V/V) as eluent. This
afforded 18a as a colorless oil (58 mg, 81%); IR (liquid film)
3388, 2918, 1600 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.84 (dd,
(43) Vogel, A. I. A Text Book of Practical Organic Chemistry, 4th
ed.; ELBS, Longman Group Limited: London, 1978; p 658.

Palladium-Catalyzed Heteroannulation
J . Org. Chem., Vol. 66, No. 1, 2001 29
as eluent, affording compound 22 (355 mg, 78%) as a colorless
oil; IR (liquid film) 3464, 3375, 2233, 1600 cm-1; 1H NMR (60
MHz, CCl4) δ 3.66 (s, 2H), 4.92 (s, 2H), 6.39-7.0 (m, 4H), 7.09-
7.46 (m, 5H). Anal. Calcd for C15H13NO: C, 80.69; H, 5.86; N,
6.27. Found: C, 80.55; H, 5.78; N, 6.18.
117.7, 121.5, 124.9, 126.2, 127.7, 128.2, 128.4, 129.1, 129.4,
130.0, 130.0, 130.1, 130.2, 134.5, 134.9, 136.1, 145.2, 148.2;
13C NMR (75 MHz, CDCl3, DEPT 135) δ 21.7, 67.6 (inverted),
117.5, 121.2, 125.9, 127.5, 127.9, 128.1, 128.8, 129.7, 129.8,
129.9. Anal. Calcd for C22H18NSO3Cl: C, 64.14; H, 4.40; N, 3.40.
Found: C, 64.26; H, 4.39; N, 3.64.
Compounds 23-27 were synthesized by following the above
procedure.
23: colorless oil; IR (liquid film) 3465, 3375, 2242, 1614 cm-1
;
36: mp 136-137 °C; IR 1668, 1597 cm-1; 1H NMR (300 MHz,
CDCl3) δ 2.35 (s, 6H), 3.96 (d, J ) 11.5 Hz, 1H), 4.35 (d, J )
11.5 Hz, 1H), 6.56 (s, 1H), 6.77 (dd, J 1 ) 8.1 Hz, J 2 ) 1.4 Hz,
1H), 6.97-7.24 (m, 6H), 7.41 (d, J ) 8.2 Hz, 2H), 7.66 (d, J )
8.1 Hz, 2H), 7.93 (dd, J 1 ) 8.1 Hz, J 2 ) 1.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 20.4, 20.5, 66.6, 116.2, 119.8, 123.8, 124.7,
125.3, 126.1, 126.9, 128.0, 128.6, 128.8, 130.0, 130.3, 133.8,
137.9, 143.5, 146.7; 13C NMR (75 MHz, CDCl3, DEPT 135) δ
21.6, 21.7, 67.8 (inverted), 117.4, 121.0, 125.9, 127.3, 128.1,
129.2, 129.8, 130.0, 131.5. Anal. Calcd for C23H21NSO3: C,
70.56; H, 5.40; N, 3.57. Found: C, 70.53; H, 5.32; N, 3.48.
1H NMR (60 MHz, CCl4) δ 3.62 (s, 2H), 4.82 (s, 2H), 6.4-6.92
(m, 4H), 7.20-7.50 (m, 4H). Anal. Calcd for C15H12NOCl: C,
69.90; H, 4.68; N, 5.43. Found: C, 69.83; H, 4.53; N, 5.31.
27: colorless sticky oil; IR (liquid film) 3466, 3375, 2241,
1605 cm-1; 1H NMR (60 MHz, CCl4) δ 3.76 (s, 4H, broad), 4.86
(s, 4H), 6.43-6.92 (m, 8H), 7.0-7.43 (m, 4H). Anal. Calcd for
C
24H20N2O2: C, 78.23; H, 5.47; N, 7.60. Found: C, 78.14; H,
5.40; N, 7.56.
Gen er a l P r oced u r e for th e Syn th esis of 28-33. Com-
pound 22 (290 mg, 1.3 mmol) was dissolved in dry dichlo-
romethane (9 mL). Then under ice-cold conditions, pyridine
(103 mg, 1.3 mmol) and tosyl chloride (248 mg, 1.3 mmol) were
added to it. The reaction mixture was then stirred for about 2
h at room temperature under nitrogen atmosphere. After the
removal of solvent, the residue was poured in 50 mL of water
and extracted with chloroform (3 × 40 mL). The combined
chloroform layer was washed with water and dried over
anhydrous Na2SO4. After the removal of solvent the residue
was purified by column chromatography over silica gel using
chloroform/petroleum ether (75/25,V/V) as eluent. The product
was finally crystallized from petroleum ether-chloroform. A
white crystalline solid 28 was obtained (350 mg, 72%); mp 111
39: mp 169 °C; IR 1668, 1597 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 2.30 (s, 6H), 4.21 (s, broad, 4H), 6.64 (s, 2H), 6.81
(dd, J 1 ) 8.4 Hz, J 2 ) 1.4 Hz, 2H), 6.92-6.97 (m, 2H), 7.05-
7.14 (m, 6H), 7.22-7.25 (m, 2H), 7.31-7.35 (m, 4H), 7.4 (s,
2H), 7.61 (d, J ) 7.4 Hz, 2H). Anal. Calcd. for C38H32N2S2O6:
C, 67.43; H, 4.76; N, 4.14. Found: C, 67.83; H, 4.49; N, 4.14.
Syn th esis of (Z)-4-Tosyl-2-[(5-u r a cilyl)m eth ylid en e]-
3,4-d ih yd r o-2H-1,4-ben zoxa zin e (40). To a magnetically
stirred solution of compound 37 (150 mg, 0.34 mmol) in dry
acetonitrile (9 mL) under argon atmosphere were added
anhydrous sodium iodide (154 mg, 1.02 mmol) and trimeth-
ylchlorosilane (0.13 mL, 1.02 mmol). The resulting mixture
was stirred at room temperature for 24 h. The solvent was
removed under reduced pressure and the residue was washed
with a few drops of sodium metabisulfite solution and then
water, filtered and dried to yield compound 40 as light yellow
solid (105 mg; 75%); crystallized from H2O-MeOH (1:9); mp
>200 °C; IR 3384, 3008, 2852, 1732, 1703, 1678, 1660, 1597
cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.36 (s, 3H), 3.84 (d, J
) 11.8 Hz, 1H), 4.66 (d, J ) 11.9 Hz, 1H), 6.70 (s, 1H) 6.79-
6.82 (m, 1H), 7.02-7.19 (m,2H), 7.33-7.44 (m, 4H), 7.65-7.68
(m,1H), 8.13 (d, J ) 4.4 Hz, 1H), 11.15 (s, broad, 1H), 11.34
(s, 1H). Anal. Calcd for C20H17N3SO5: C, 58.38; H, 4.16; N,
10.21. Found: C, 58.24; H, 4.20; N, 10.23.
°C; IR 3259, 1599 cm-1 1H NMR (60 MHz, CCl4) δ 2.16 (s,
;
3H), 4.7 (s, 2H), 6.75-7.72 (m, 14H). Anal. Calcd for C22H19
-
NSO3: C, 70.00; H, 5.07; N, 3.71. Found: C, 69.84; H, 4.99; N,
3.58.
29: mp 109 °C; IR 3267, 1597 cm-1; 1H NMR (60 MHz, CCl4)
δ 2.23 (s, 3H), 4.70 (s, 2H), 6.80-7.82 (m, 13H). Anal. Calcd
for C22H18NSO3Cl: C, 64.14; H, 4.40; N, 3.40. Found: C, 64.31;
H, 4.47; N, 3.82.
33: mp 64 °C; IR 3261, 1598 cm-1; 1H NMR (60 MHz, CCl4)
δ 2.23 (s, 6H), 4.60 (s, 4H), 6.70-7.33 (m, 14H), 7.36-7.75 (m,
8H). Anal. Calcd for C38H32N2S2O6: C, 67.43; H, 4.76; N, 4.14.
Found: C, 67.30; H, 4.71; N, 4.12.
Typ ica l P r oced u r e for th e Syn th esis of (Z)-3-Ben -
zylid en e-4-t osyl-3,4-d ih yd r o-2H-1,4-b en zoxa zin e 34. A
mixture of 28 (250 mg, 0.66 mmol), CuI (25 mg, 0.13 mmol),
K2CO3 (229 mg, 1.65 mmol), and Bu4NBr (213 mg, 0.66 mmol)
in dry acetonitrile (11 mL) was stirred for about 15 min under
argon atmosphere. It was then refluxed for about 12 h under
argon atmosphere. After removal of acetonitrile under reduced
pressure, the reaction mixture was poured in 50 mL of water
and extracted with chloroform (3 × 40 mL). The combined
chloroform layer was washed with water and dried over
anhydrous Na2SO4. After removal of solvent, the residue was
chromatographed over silica gel eluting with chloroform/
petroleum ether (75/25,V/V), affording compound 34 (220 mg,
88%) as a colorless solid. It was finally crystallized from
Similar reaction condition was used for the synthesis of
compound 41 from 18g.
Compound 41: (70.00%); crystallized from H2O-MeOH (9:
1), mp > 200 °C; IR 3300, 3037, 2868, 1708, 1686, 1662, 1606
cm-1; 1H NMR (300 MHz, DMSO d6) δ 2.50 (m, 2H), 2.92 (dd,
J 1 ) 11.8 Hz, J 2 ) 7.5 Hz, 1H), 3.19-3.26 (m, 2H), 4.11 (m,
1H), 6.43-6.48 (m, 1H), 6.54-6.68 (m, 3H), 7.30 (d, J ) 5.28
Hz, 1H), 10.74 (d, J ) 4.35 Hz, 1H), 11.09 (s, 1H). For correct
analysis the analytical sample need to be dried at 80 °C/0.5
mm of Hg for 6 h. Anal. Calcd for C13H13N3O3: C, 60.22; H,
5.05; N, 16.20. Found: C, 60.11; H, 5.17; N, 16.21.
petroleum ether-chloroform; mp 176 °C; IR 1678, 1599 cm-1
;
1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 4.01 (d, J ) 11.4
Hz, 1H), 4.37 (d, J ) 11.4 Hz, 1H), 6.58 (s, 1H), 6.78 (d, J )
8.1 Hz,1H), 6.97-7.14 (m, 4H), 7.26-7.42 (m, 5H), 7.73 (d, J
) 7.2 Hz, 2H), 7.92 (dd, J 1 ) 8.1 Hz, J 2 ) 1.2 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 22.0, 68.1, (3J CH ) 4.73 Hz), 117.7,
121.4, 125.2, 126.2, 127.6, 127.8, 128.4, 128.8, 129.3, 130.1,
130.3, 131.7, 134.3, 135.2, 145.0, 148.3; 13C NMR (75 MHz,
CDCl3, DEPT 135) δ 21.7, 67.8 (inverted), 117.4; 121.1, 126.0,
127.3, 128.1, 128.5, 129.0, 129.8, 130.0, 131.5. Anal. Calcd for
Ack n ow led gm en t. Thanks are due Dr. Chinmay
Chowdhury for taking the mass spectra. Thanks are also
due to Mr. Kausik Das for helping with preparing the
manuscript.
C
22H19NSO3: C, 70.00; H, 5.07; N, 3.71. Found: C, 69.86; H,
5.13; N, 3.49.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
analytical data for compounds 8c, 8e, 8g-k , 9b, 9c, 9i, 9j,
18e, 18g, 18h , 24-26, 30-32, 37, and 38 (22 compounds). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Sim ila r Rea ction Con d ition s w er e Em p loyed for th e
Syn th esis of 35-39
35: mp 160 °C; IR 1670, 1597 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 2.35 (s, 3H), 4.07 (d, J ) 10.5 Hz, 1H), 4.39 (d, J )
10.6 Hz, 1H), 6.51 (s, 1H), 6.80 (dd, J 1 ) 10.8 Hz, J 2 ) 1.0 Hz,
1H), 6.98-7.30 (m, 6H), 7.40-7.66 (m, 4H), 7.87 (dd, J 1 ) 8.1
Hz, J 2 ) 1.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 22.0 67.9,
J O000826J